Therapeutic strategies for targeting BRAF in human cancer Journal Article
| Authors: | Pratilas, C. A.; Solit, D. B. |
| Article Title: | Therapeutic strategies for targeting BRAF in human cancer |
| Abstract: | Constitutive ERK activation is a common finding in human cancer and is often the result of activating mutations of BRAF and RAS. BRAF missense mutations occur in approximately 8% of human tumors, most frequently in melanoma, papillary thyroid cancer and colon cancer. Mutations in BRAF have been found predominantly in tumors in which RAS is commonly mutated but concurrent mutations of both BRAF and RAS are extremely rare. Though over 40 different kinase domain mutations in BRAF have been identified, a single base-pair substitution in exon 15 at codon 600 (V600E) is found in over 80% of cases. These mutations cluster in the glycine-rich loop and activation segments of the kinase and are predicted to induce kinase activation by disrupting the inhibitory glycine-rich loop/activation segment interaction which characterizes the inactive conformation. The majority of mutations identified cause constitutive kinase activation with the V600E mutation demonstrating approximately 500-fold greater kinase activity than wild-type BRAF. Supporting its classification as an oncogene, V600E BRAF stimulates ERK signaling, induces proliferation and is capable in model systems of promoting transformation. However, BRAF mutations are common in nevi and colon polyps suggesting that BRAF mutation alone is insufficient for tumorigenesis and additional mutations are required for cancer development. Though such data suggest that BRAF mutation is likely an early initiating event in tumors such as melanoma and colon cancer, preclinical studies suggest that tumors with V600E BRAF mutation remain dependent upon BRAF for proliferation and survival. Given its frequent occurrence in human cancer and the continued requirement for BRAF activity in tumors with BRAF mutation, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. The first generation of RAF inhibitors, including sorafenib, were notable for their lack of specificity and potency for RAF and these agents have shown limited efficacy in tumors with a high incidence of BRAF mutation such as melanoma. Novel inhibitors of the pathway with greater selectivity for BRAF and MEK are now in Phase 1 and 2 clinical trials with promising early results. To maximize the likelihood of success with these agents, clinical trials enriched with patients whose tumors possess BRAF and RAS mutations have been proposed. © 2007 Bentham Science Publishers Ltd. |
| Keywords: | signal transduction; mitogen activated protein kinase; cancer survival; unclassified drug; gene cluster; missense mutation; mutation, missense; clinical trial; review; sorafenib; cancer growth; drug dose comparison; drug efficacy; nonhuman; unspecified side effect; antineoplastic agents; paclitaxel; protein domain; neoplasms; carboplatin; unindexed drug; melanoma; nevus; mitogen activated protein kinase inhibitor; protein kinase inhibitor; drug potency; enzyme activation; drug specificity; mutational analysis; carcinogenesis; colon cancer; protein farnesyltransferase inhibitor; heat shock protein 90 inhibitor; malignant neoplastic disease; base pairing; ras protein; drug bioavailability; optimal drug dose; ras proteins; genes, ras; codon; malignant transformation; b raf kinase; colon polyp; mitogen-activated protein kinase kinases; raf kinases; glycine; proto-oncogene proteins b-raf; plx 4032; enzyme conformation; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; geldanamycin; radicicol; map kinase; 2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; nucleic acid base substitution; chir 265; xl 281; cnf 2024; snx 5542; raf 265; sb 590885; low malignant po; pi3-kinase; raf mutations; 17 allylamino geldanamycin; arry 142886; azd 6244; exel 2819; hypothemycin derivative; letx; ver 49009 |
| Journal Title: | Reviews on Recent Clinical Trials |
| Volume: | 2 |
| Issue: | 2 |
| ISSN: | 1574-8871 |
| Publisher: | Bentham Science Publishers |
| Date Published: | 2007-05-01 |
| Start Page: | 121 |
| End Page: | 134 |
| Language: | English |
| DOI: | 10.2174/157488707780599393 |
| PUBMED: | 18473997 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 17 November 2011" - "Source: Scopus" |
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